This application addresses the broad Challenge Area (15): Translational Science and the specific Challenge Topic 15-DK-102: Develop improved animal models of NIDDK diseases. Metabolic homeostasis plays a central role in all aspects of postembryonic life, allowing animals to balance their dietary intake with the energy needs required for day-to-day survival. Conversely, misregulation of metabolism can lead to obesity and type 2 diabetes, which are critical risk factors for human disease, including cardiovascular disorders and cancer. The goal of our research is to use the fruit fly, Drosophila melanogaster, as a simple model system to define the central regulatory pathways that control metabolism and maintain energy homeostasis in all higher organisms, including humans. Our experimental approach exploits the unique strengths of Drosophila as a model system by conducting an open-ended genetic screen in the intact animal. This proposal arises from our ongoing studies of nuclear receptor signaling in Drosophila and the central role of these factors in maintaining metabolic homeostasis. Genetic studies have demonstrated that the nuclear receptor DHR96 is required to maintain appropriate triacylglycerol (TAG) levels in the animal. DHR96 mutants are viable, have low levels of TAG, and are sensitive to starvation, correlating with the misregulation of key lipid metabolic genes. We have discovered that the starvation sensitivity of DHR96 mutants can be rescued by introducing second-site mutations in genes that increase TAG levels, such as the adipose triglyceride lipase gene or the adipokinetic hormone receptor gene (which acts like glucagon to drive lipolysis). This observation provides a framework for identifying new genes that control lipid metabolism. We propose to exploit the DHR96 mutant as a sensitized genetic background for conducting open-ended genetic screens with the aim of identifying mutations that rescue its starvation sensitivity. Our preliminary data indicate that this screen should uncover a range of genes involved in many aspects of lipid metabolism, including genes which, when mutated, lead to obesity. Recently developed methods for efficient single-gene disruption by transposon mutagenesis will facilitate the screen and allow rapid gene identification. These studies provide a new basis for using Drosophila as means of extending our understanding of key lipid metabolic pathways that impact human health. Genetic screens represent one of the most powerful and important advantages of working in Drosophila, and offer a way to expand our understanding of specific biological pathways in new and unexpected directions. This approach has had a major impact on our understanding of human health through the delineation of the fundamental pathways that dictate embryonic development and the discovery of central signaling pathways, such as Notch, Wnt, and hedgehog signaling. We propose to exploit this strength of the fly toward the discovery of novel genes that impact lipid metabolism. We will focus our studies on newly identified Drosophila genes that have close homologs in mice and humans to facilitate the translation of our discoveries into vertebrate systems. Our long-term goal is to provide new candidates for mouse gene knockout studies and human disease gene mapping. In this way we hope to use the fly as a tool for gene discovery and extend these advances toward a better understanding of the causes of human metabolic disorders. PUBLIC HEALTH RELEVANCE: The dramatic rise in metabolic disorders, such as diabetes and obesity, poses a major health risk to the world population. This proposed research will use the fruit fly, Drosophila, as a simple genetic model system to define the fundamental mechanisms that control lipid metabolism, with the goal of providing new directions for understanding and treating human metabolic disorders.